This application is a National Stage application under 35 U.S.C. xc2xa7371 of PCT/EP99/02045 filed Mar. 24, 1999, which claims priority from EP 98.201.020.9, filed Apr. 1, 1998.
The present invention concerns pyridine derivatives having phosphodiesterase IV (PDE IV) and cytokine inhibiting activity and their preparation; it further relates to compositions comprising them, as well as their use as a medicine.
W095/04045 generically discloses 2-pyridinyl-1-[dialkyloxypiridinyl]-ethanone derivates useful for treating phosphodiesterase IV related disorders. WO 96/31485 describes a number of 1,3-dihydro-1-(phenylalkyl)-2H-imidazol-2-one derivatives having PDE IV and cytokine inhibiting activity.
The compounds of the present invention are structurally different from art-known PDE IV inhibitors. They have therapeutical utility in the treatment of disease states related to an abnormal enzymatic or catalytic activity of PDE IV, and/or disease states related to a physiologically detrimental excess of cytokines, in particular allergic, atopic and inflammatory diseases. The present compounds have an improved pharmacological profile with little or no gastro-intestinal side-effects, which are often associated with art-known PDE IV inhibitors.
The present invention concerns pyridine derivatives having the formula 
wherein:
L is hydrogen; C1-6alkyl; C1-6alkyl substituted with one or two substituents selected from the group consisting of hydroxy, C1-4alkyloxy, C1-4alkyloxycarbonyl, mono- and di(C1-4alkyl)amino, aryl and Het2; C3-6alkenyl; C3-6alkenyl substituted with aryl; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; piperidyl; piperidyl substituted with C1-4alkyl or arylC1-4alkyl; C1-6alkylsulfonyl or arylsulfonyl;
xe2x80x94Axe2x80x94Bxe2x80x94 is a bivalent radical of formula:
D is O or NR6;
Q is a radical of the formula 
R1 is hydrogen or C1-4alkyl;
or R1 and R2 together may form a bivalent radical of formula xe2x80x94(CH2)mxe2x80x94 wherein m is 1, 2, 3 or 4;
R2 is hydrogen; halo; C1-6alkyl; trifluoromethyl; C3-6cycloalkyl; carboxyl; C1-4alkyloxycarbonyl; C3-6cycloalkylaminocarbonyl; aryl; Het1; or C1-6alkyl substituted with cyano, amino, hydroxy, C1-4alkylcarbonylamino, aryl or Het1; or
R2 is a radical of formula:
xe2x80x94Oxe2x80x94R9 (cxe2x88x921); or
xe2x80x94NHxe2x80x94R10 (cxe2x88x922);
R3 is hydrogen, halo, hydroxy, C1-6alkyl or C1-6alkyloxy; or
R2 and R3 taken together may form a bivalent radical of formula:
wherein n is 2, 3, 4 or 5;
R4 and R5 are each independently selected from hydrogen or C1-4alkyl;
R6 is hydrogen, C1-4alkyl or cyano;
R7 and R8 each independently are hydrogen; C1-6alkyl; difluoromethyl; trifluoromethyl; C3-6cycloalkyl; a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms each independently selected from oxygen, sulfur or nitrogen; indanyl; 6,7-dihydro-5H-cyclopentapyridyl; bicyclo[2.2.1]-2-heptenyl; bicyclo[2.2.1]heptanyl; C1-6alkylsulfonyl; arylsulfonyl; or C1-6alkyl substituted with one or two substituents each independently selected from aryl, pyridyl, thienyl, furanyl, indanyl, 6,7-dihydro-5H-cyclopentapyridyl, C3-7cycloalkyl and a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen;
R9 is hydrogen; C1-6alkyl; C1-6alkyl substituted with hydroxy, carboxyl, C1-4alkyloxycarbonyl, amino, mono- or di(C1-4alkyl)amino, Het1 or aryl;
R10 is hydrogen; C1-6alkyl; C1-4alkylcarbonyl; C1-6alkyl substituted with hydroxy, carboxyl, C1-4alkyloxycarbonyl, amino, mono- or di(C1-4alkyl)amino, Het1 or aryl;
R11 is hydrogen, C1-6alkyl, C1-6alkylsulfonyl or p-toluenesulfonyl;
aryl is phenyl or phenyl substituted with one, two or three substituents each independently selected from halo, hydroxy, C1-4alkyl, C1-4alkyloxy, C3-6cycloalkyl, trifluoromethyl, amino, nitro, carboxyl, C1-4alkyloxycarbonyl and C1-4alkylcarbonylamino;
Het1 is pyridyl; pyridyl substituted with C1-4alkyl; furanyl; furanyl substituted with C1-4alkyl; thienyl; thienyl substituted with C1-4alkylcarbonylamino; hydroxypyridyl, hydroxypyridyl substituted with C1-4alkyl or C1-4alkoxyC1-4alkyl; imidazolyl; imidazolyl substituted with C1-4alkyl; thiazolyl; thiazolyl substituted with C1-4alkyl; oxazolyl; oxazolyl substituted with C1-4alkyl; isoquinolinyl; isoquinolinyl substituted with C1-4alkyl; quinolinonyl; quinolinonyl substituted with C1-4alkyl; morpholinyl; piperidyl; piperidyl substituted with C1-4alkyl, C1-4alkyloxycarbonyl or arylC1-4alkyl; piperazinyl; piperazinyl substituted with C1-4alkyl, C1-4alkyloxycarbonyl or arylC1-4alkyl; and
Het2 is morpholinyl; piperidyl; piperidyl substituted with C1-4alkyl or arylC1-4alkyl; piperazinyl; piperazinyl substituted with C1-4alkyl or arylC1-4alkyl; pyridyl; pyridyl substituted with C1-4alkyl; furanyl; furanyl substituted with C1-4alkyl; thienyl or thienyl substituted with C1-4alkyl or C1-4alkylcarbonylamino;
the N-oxide forms, the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof.
Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention. In particular, compounds of formula (I) wherein L is hydrogen may exist in their corresponding tautomeric form.
In R7 and R8, the saturated 5-, 6- or 7-membered heterocycles containing one or two heteroatoms selected from oxygen, sulfur or nitrogen may suitably be selected from heterocycles such as, for example, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, morpholinyl, piperidyl, piperazinyl and tetrahydropyranyl. Said heterocyclic radicals are attached to the oxygen atom or the C1-10alkyl radical by any carbon atom or, where appropriate, by a nitrogen atom.
Also in R7 and R8, the term 6,7-dihydro-5H-cyclopentapyridyl is meant to represent 6,7hydro-5H-cyclopenta[b]pyridyl or 6,7-dihydro-5H-cyclopenta[c]pyridyl and may be attached to the remainder of the molecule by any of the aliphatic or aromatic carbon atoms.
As used herein the term halo is generic to fluoro, chloro, bromo and iodo; the term C1-4alkyl is meant to include straight chained or branched saturated hydrocarbons having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, 1-methylethyl, 1,1dimethylethyl, propyl, 2-methylpropyl and butyl; the term C1-6alkyl is meant to include C1-4alkyl and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, 2-methylbutyl, pentyl, hexyl and the like; the term C10alkyl is meant to include C1-6alkyl and the higher homologues thereof having from 7 to 10 carbon atoms such as, for example, heptyl, octyl, nonyl, decyl, I -methylhexyl, 2-methylheptyl and the like; the term C3-6alkenyl defines straight and branch chained hydrocarbon radicals containing one double bond and having from 3 to 6 carbon atoms such as, for example, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl and the like; and the carbon atom of said C3-6alkenyl being connected to a nitrogen atom preferably is saturated; the term C3-6cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; the term C3-7cycloalkyl is meant to include C3-6cycloalkyl and cycloheptyl; the term C1-4alkanediyl is meant to include straight chained and branched saturated bivalent hydrocarbon radicals having from 1 to 4 carbon atoms, such as, for example, methylene, 1,2-ethanediyl, 1,1-ethanediyl, 1,3-propanediyl, 1,2-propanediyl, 1,4-butanediyl, 2-methyl-1,3-propanediyl and the like.
As used in the foregoing definitions and hereinafter, haloC1-4alkanediyl is defined as mono- or polyhalosubstituted C1-4alkanediyl, in particular C1-4alkanediyl substituted with one or more fluoro atoms.
The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the acid addition salt forms which can conveniently be obtained by treating the base form of the compounds of formula (I) with appropriate acids such as inorganic acids, for example, hydrohalic acid, e.g. hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like acids; or organic acids, such as, for example, acetic, hydroxy-acetic, propanoic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids. Conversely, said acid addition salt forms can be converted in the free base forms by treatment with an appropriate base.
The compounds of formula (I) containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
The term addition salt also comprises the hydrates and solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
The N-oxide forms of the compounds of formula (I) are meant to comprise those compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.
The term xe2x80x9cstereochemically isomeric formsxe2x80x9d as used hereinbefore defines all the possible stereoisomeric forms which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centers may have the R- or S-configuration, and the xe2x95x90NR6 and substituted C3-6alkenyl moieties may have the E- or Z-configuration.
Whenever used hereinafter, the term compounds of formula (I) is meant to include also the N-oxide forms, the pharmaceutically acceptable acid or base addition salts and all stereoisomeric forms.
A special group of compounds includes those compounds of formula (I) wherein R7 and R8 each independently are hydrogen; C1-6alkyl; C3-6cycloalkyl; difluoromethyl; trifluoromethyl; a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen; indanyl; bicyclo[2.2.1]-2-heptenyl; bicyclo[2.2.1]heptanyl; C1-6alkylsulfonyl; arylsulfonyl; or C1-10alkyl substituted with one or two substituents each independently selected from aryl, pyridyl, thienyl, furanyl, C3-7cycloalkyl and a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen.
Interesting compounds are those compounds of formula (I) wherein R2 and R3 are each independently C1-6alkyl; C3-6cycloalkyl; difluoromethyl; a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen; indanyl; or C1-10alkyl substituted with aryl, indanyl, 6,7-dihydro-5H-cyclopentapyridyl or C3-6cycloalkyl.
Also interesting compounds are those compounds of formula (I) wherein R2 and R3 are each independently hydrogen, hydroxy or C1-6alkyl.
Particular compounds are those compounds of formula (I) wherein R7 is cyclopentyl, tetrahydrofuranyl, cyclopropylmethyl, 5-phenylpentyl or indanyl; R8 is hydrogen, methyl or difluoromethyl; R2 is hydrogen or methyl; R3 is hydrogen, hydroxy or methyl and R1, R4, R5 and L are hydrogen.
Most preferred are the following compounds:
[1-[2-[6-(cyclopentyloxy)-5-methoxy-2-pyridinyl]propyl]-1,3-dihydro-2H-imidazol-2-ylidene]cyanamide; and [1-[2-[6-(cyclopentyloxy)-5-methoxy-2-pyridinyl]propyl]-1,3-dihydro-2H-imidazol-2-one, their N-oxides, their stereochemically isomeric forms and their pharmaceutically acceptable addition salts.
Whenever used hereinafter, R1 to R11, L, D, Q and xe2x80x94Axe2x80x94Bxe2x80x94 are defined as under formula (I) unless otherwise indicated.
Compounds of formula (I) wherein xe2x80x94Axe2x80x94Bxe2x80x94 is a radical of formula (a-1) and L is hydrogen, said compounds being represented by formula (I-a-1), can conveniently be prepared by cyclization of an intermediate of formula (II) or a functional derivative thereof in the presence of a suitable acid such as, for example, hydrochloric acid. 
Said cyclization may be performed in a reaction inert solvent such as, for example, tetrahydrofuran, 1,4-dioxane or a mixture thereof. Stirring and heating may enhance the rate of the reaction.
In this and the following preparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, trituration and chromatography.
In particular, compounds of formula (I-a-1) wherein R2 is hydroxy, said compounds being represented by formula (I-a-1-1), may be prepared by cyclization of an intermediate of formula (II-1) wherein P is hydrogen or, preferably, is a trimethylsilyl protecting group or a functional derivative thereof, in a manner analogous to the one described for the preparation of a compound of formula (I-a-1) from an intermediate of formula (II). 
The compounds of formula (I) can also be converted into each other following art-known procedures of functional group transformation.
For example, compounds of formula (I) wherein L is other than hydrogen, said compounds being represented by formula (I-b), may be prepared by reacting a compound of formula (I-a) with Lxe2x80x2-W2 (III), wherein Lxe2x80x2 is the same as L defined under formula (I) but other than hydrogen and W2 is a reactive leaving group such as, for example, a halogen atom. 
Also art-known addition reactions may be used to convert compounds of formula (I-a) into compounds of formula (I-b).
Compounds of formula (I-a) wherein xe2x80x94Axe2x80x94Bxe2x80x94 is a radical of formula (a-2), said compounds being represented by formula (I-a-2), can be prepared by hydrogenation of compounds of formula (I-a) wherein xe2x80x94Axe2x80x94Bxe2x80x94 is a radical of formula (a-1), said compounds being represented by formula (I-a-1), using art-known hydrogenation techniques. For instance, hydrogen in the presence of a suitable catalyst such as, for example, palladium or platinum supported on for instance charcoal may be used as an appropriate hydrogenation agent. 
Compounds of formula (I) wherein R2 is hydroxy and R3 is methyl, said compounds being represented by formula (I-a-1-2), may be prepared by oxidizing a compound of formula (I) wherein R2 is hydroxy and R3 is hydrogen, said compounds being represented by formula (I-a-1-3) with a suitable oxidizing agent, such as, for example, ethanediol dichloride, in a suitable reaction inert solvent, such as, for example, dichloromethane, in the presence of a suitable base, such as, for example, triethylamine, followed by reacting the thus formed intermediate with a Grignard reagent. 
The compounds of formula (I) may also be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with 3-phenyl-2-(phenylsulfonyl)oxaziridine or with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. t-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
Intermediates mentioned hereinabove may be prepared following art-known techniques.
In particular, intermediates of formula (II) wherein D is Nxe2x80x94CN, said compounds being represented by formula (II-a) may be prepared by first reacting an amine of formula (IV) with dimethyl cyanocarbonimidodithioate or diphenyl cyanocarbonimidate or a functional derivative thereof. Said reaction can conveniently be performed in a reaction inert solvent such as, for example, dichloromethane, benzene or toluene, optionally cooled on an ice-bath, and in the presence of a base such as, for example, triethylamine or sodiumbicarbonate. The thus obtained intermediate may be subsequently reacted with an intermediate of formula (V) or a functional derivative thereof, to form an intermediate of formula (II-a). Said reaction can conveniently be performed in a reaction inert solvent such as, for example, 1,4-dioxane, in the presence of a base such as, for example, triethylamine, and optionally in the presence of a catalyst such as, for example, N,N-dimethyl-pyridinamine. Stirring and elevated temperatures may enhance the rate of the reaction. 
Alternatively, the above reaction may be performed in reverse order, i.e. first react an intermediate of formula (V) with dimethyl cyanocarbonimidodithioate or diphenyl cyanocarbonimidate or a functional derivative thereof, and subsequently react the thus formed intermediate with an amine of formula (IV).
Intermediates of formula (II) wherein D is oxygen, said compounds being represented by formula (II-b), may be prepared by first N-acylating an amine of formula (IV) with phenyl chloroformate or a functional derivative thereof. Said N-acylation can conveniently be performed in a reaction inert solvent such as, for example, dichloromethane, benzene or toluene, optionally cooled on an ice-bath, and in the presence of a base such as, for example, triethylamine or sodiumbicarbonate. The thus obtained intermediate may be subsequently reacted with 2,2-(diC1-4alkyloxy) ethanamine (V) or a functional derivative thereof, to form an intermediate of formula (II-b). Said reaction can conveniently be performed in a reaction inert solvent such as, for example, 1,4-dioxane, in the presence of a base such as, for example, triethylamine, and optionally in the presence of a catalyst such as, for example, N,N-dimethyl-pyridin- amine. Stirring and elevated temperatures may enhance the rate of the reaction. 
Also, intermediates of formula (II-b) may be directly formed by reacting an intermediate of formula (IV) with a suitable reagent such as, for example, N-[2,2-di-(C1-4alkyl)ethyl]-1H-imidazole-1-carboxamide or a functional derivative of any one of said reagents. 
In particular, intermediates of formula (II-b), wherein R2 is a hydroxy group or, preferably, a protected hydroxy group, the protective group P being a trimethylsilyl protecting group or a functional derivative thereof, said intermediates being represented by formula (II-b-1), may be prepared by reacting an intermediate of formula (IV) wherein R2 is a hydroxy group or, preferably, a protected hydroxy group, the protective group P being a trimethylsilyl protecting group or a functional derivative thereof, said intermediates being represented by formula (IV-1), with N-[2,2-di(C1-4alkyl)ethyl]-1H-imidazole-1-carboxamide or a functional derivative thereof. 
Intermediates of formula (IV) wherein R1 is hydrogen, said intermediates being represented by formula (IV-a), may be prepared by reducing the unsaturated carbon-nitrogen bond in the intermediates of formula (VI) with a suitable reducing agent such as, for example, lithium aluminium hydride or hydrogen in the presence of a catalyst such as, for example, Raney nickel. The cyanide moiety in the intermediates of formula (VI) may also be replaced by a functional derivative thereof such as, for example, an oxime moiety. 
The synthesis of some of the intermediates of formula (VI) is described in WO 95/04045, WO 96/31485, WO 97/03967 and WO 98/14432.
Some of the compounds of formula (I) and some of the intermediates in the present invention contain at least one asymmetric carbon atom. Pure stereochemically isomeric forms of said compounds and said intermediates can be obtained by the application of art-known procedures. For example, diastereomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereomeric salts or compounds; then physically separating said mixtures of diastereomeric salts or compounds by, for example, selective crystallization or chromatographic techniques, e.g. liquid chromatography and the like methods; and finally converting said separated diastereomeric salts or compounds into the corresponding enantiomers.
Pure stereochemically isomeric forms of the compounds of formula (I) may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the intervening reactions occur stereo-specifically. The pure and mixed stereochemically isomeric forms of the compounds of formula (I) are intended to be embraced within the scope of the present invention.
An alternative manner of separating the enantiomeric forms of the compounds of formula (I) and intermediates involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase.
The compounds of formula (I), the N-oxide forms, pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, are potent inhibitors of the phosphodiesterase (PDE) isoenzymes of family IV (cAMP-specific family).
cAMP (adenosine cyclic 3xe2x80x2,5xe2x80x2-monophosphate) is a key second messenger, the concentration of which affects particular cell activities through activation of enzymes such as kinases. PDE IV is known to hydrolyse cAMP to its corresponding inactive 5xe2x80x2-monophosphate metabolite. Hence, inhibition of PDE IV leads to an elevation of cAMP levels in particular cells such as the respiratory smooth muscle cell and a wide variety of inflammatory cells, i.e. certain lymphocytes, e.g. basophils, neutrophils and eosinophils, monocytes and mast-cells. A number of allergic, atopic and inflammatory diseases are deemed to be caused by higher-than-normal PDE IV concentrations which result in low cAMP levels and hypersensitivity of the thus affected cells for excitatory stimuli. (Examples of said hypersensitivity are for example, excessive histamine release from basophils and mast cells or excessive superoxide anion radical formation by eosinophils.) Hence, the present compounds having potent phosphodiesterase IV inhibitory properties are deemed useful agents in alleviating and/or curing allergic, topic and inflammatory diseases. The functional effects of PDE IV inhibitors are e.g. respiratory smooth muscle relaxation, bronchodilation, platelet aggregation inhibition and inhibition of white blood cell mediator release. Examples of allergic diseases are bronchial asthma, cheilitis, conjunctivitis, contact dermatitis and eczema, irritable bowel disease, deshydroform eczema, urticaria, vasculitis, vulvitis; examples of atopic diseases are dermatitis and eczema, winterfeet, asthma, allergic rhinitis; and related afflictions are, for example, psoriasis and other hyperproliferative diseases.
The compounds of the present invention also have cytokine inhibitory activity. A cytokine is any secreted polypeptide that affects the function of other cells by modulating interactions between cells in the immune or inflammatory response. Examples of cytokines are monokines and lymphokines and they may be produced by a wide variety of cells. For instance, a monokine is generally referred to as being produced and secreted by a mononuclear cell, such as a macrophage and/or monocyte but many other cells produce monokines, such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells, epideral keratinocytes, and 0-lymphocytes. Lymphokines are generally referred to as being produced by lymphocyte cells. Examples of cytokines include Interleukin-1(IL-1), Interleukin-2(IL-2), Interleukin-6(IL-6), Interleukin-8(IL-8), alpha-Tumor Necrosis Factor (xcex1TNF) and beta-Tumor Necrosis Factor (xcex2TNF).
The cytokine specifically desired to be inhibited is xcex1TNF. Excessive or unregulated TNF production is implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusion injury, graft versus host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn""s disease, ulcerative colitis, or pyresis.
The present invention thus also relates to compounds of formula (I) as defined hereinabove, their N-oxides, pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof for use as a medicine, in particular for use as a medicine for treating disease states related to an abnormal enzymatic or catalytic activity of PDE IV, and/or disease states related to a physiologically detrimental excess of cytokines, in particular allergic, atopic and inflammatory diseases, more in particular asthmatic and atopic diseases, most particular atopic dermatitis. Thus the compounds of the present invention may be used for the manufacture of a medicament for treating atopic or asthmatic diseases, more in particular atopic dermatitis.
The present invention also relates to a method of treating warm-blooded animals suffering from disease states related to an abnormal enzymatic or catalytic activity of PDE IV, and/or disease states related to a physiologically detrimental excess of cytokines, in particular allergic, atopic and inflammatory diseases, more in particular asthmatic and atopic diseases, most particular atopic dermatitis. Said method comprises the administration of a therapeutically effective amount of a compound of formula (I) or a N-oxide form, a pharmaceutically acceptable acid or base addition salt or a stereochemically isomeric form thereof in admixture with a pharmaceutical carrier.
In general it is contemplated that an effective daily amount would be from 0.01 mg/kg to 10 mg/kg body weight. It is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount range mentioned hereinabove are therefore guidelines only and are not intended to limit the scope or use of the invention to any extent.
The PDE IV inhibitory activity of the compounds of formula (I) may be demonstrated in the test xe2x80x9cInhibition of recombinant human mononuclear lymphocyte (MNL) phosphodiesterase type IV B produced in insect cells with a baculovirus vectorxe2x80x9d. Several in vivo and in vitro tests may be used to demonstrate the usefulness of the compounds of formula (I) in treating the described allergic, atopic and inflammatory diseases. Such tests are for instance, xe2x80x9cBronchoconstriction of the guinea pig trachea in vitroxe2x80x9d, xe2x80x9cBronchoconstriction of the guinea pig trachea in vivoxe2x80x9d and the in vivo tests xe2x80x9cArachidonic acid induced pinnal inflammation in micexe2x80x9d, xe2x80x9cTPA induced ear inflammation in micexe2x80x9d, and xe2x80x9cDelayed type hypersensitivity in micexe2x80x9d.
Further, the present compounds have only very low inhibitory activity on the phosphodiesterase isoenzymes of family III (cGMP-inhibited family). Inhibition of, in particular, PDE III leads to an elevation of cAMP in the cardiac muscle, thereby causing effects on the contractile force of the heart as well as on the relaxation of the heart. In the treatment of the described allergic, atopic and inflammatory diseases, cardiovascular effects clearly are undesired. Hence, as the present compounds inhibit PDE IV at much lower concentrations as they inhibit PDE III, their therapeutic use may be adjusted to avoid cardiovascular side-effects.
Art-known PDE IV inhibitors often cause adverse gastro-intestinal side effects. Most of the present compounds, however, have few effects on the gastro-intestinal tract, which may be demonstrated in the test xe2x80x9cGastric emptying of a caloric meal in ratsxe2x80x9d.
The designation PDE III and IV as used herein refers to the classification by J. A. Beavo and D. H. Reifsnyder, TIPS Reviews, Apr. 1990. pp. 150-155.
The cytokine inhibitory activity of the compounds of formula (I), such as the inhibition of xcex1TNF production, may be demonstrated in the in vitro test xe2x80x9cCytokine production in human whole blood culturesxe2x80x9d.
In addition, the compounds of the present invention are expected to show no or little endocrinological side-effects. This may be evidenced by, for instance, the xe2x80x9cTestosterone in vivoxe2x80x9d test, the xe2x80x9cIn vitro inhibition of the aromatase activityxe2x80x9d-test and the xe2x80x9cIn vivo inhibition of the aromatase activityxe2x80x9d-test.
In view of their useful PDE IV and cytokine inhibiting properties, the subject compounds may be formulated into various pharmaceutical compositions for administration purposes comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of a compound of formula (I). To prepare the pharmaceutical compositions of this invention, a therapeutically effective amount of the particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally, topically, percutaneously, by inhalation or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral unit dosage form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment or cream. As appropriate compositions for topical application there may be cited all compositions usually employed for topically administering drugs e.g. creams, gellies, dressings, shampoos, tinctures, pastes, lotions, solutions, ointments, salves, powders and the like. Application of said compositions may be by aerosol, e.g. with a propellant such as nitrogen, carbon dioxide, a freon, or without a propellant such as a pump spray, drops, lotions, or a semisolid such as a thickened composition which can be applied by a swab. In particular, semisolid compositions such as salves, creams, gellies, ointments and the like will conveniently be used.
In order to enhance the solubility and/or the stability of the compounds of formula (I) in pharmaceutical compositions, it can be advantageous to employ xcex1-, xcex2- or xcex3-cyclodextrins or their derivatives, in particular hydroxyalkyl substituted cyclodextrins, e.g. 2-hydroxypropyl-xcex2-cyclodextrin. Also co-solvents such as alcohols may improve the solubility and/or the stability of the compounds of formula (I) in pharmaceutical compositions. In the preparation of aqueous compositions, addition salts of the subject compounds are obviously more suitable due to their increased water solubility.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.